This proposal is designed to combine the candidate's strong clinical experience in hematology/oncology with molecular biology, and allow for the successful transition of the investigator to an independent physician-scientist. This work will be conducted under the supervision of Dr. Timothy Ley, whose laboratory has considerable experience in leukemia genetics, transgenic technology, and analysis of murine hematopoiesis. An advisory committee consisting of nationally recognized experimental hematologist has been assembled to provide scientific and career advice. Core facilities of the Washington University Cancer Center, in addition to the scientific and clinical resources of the School of Medicine and Barnes-Jewish Hospital, will provide a rich environment to facilitate this candidate's long-term goal to become an independent investigator at an academic medical center. The goal of this work is to define the importance of an interstitial deletion on chromosome 2 [del(2)] for the progression of murine acute promyelocytic leukemia (APL). To accomplish this goal, we will recreate the chromosome 2 deletion in the mouse, and study the effect on leukemia progression. Four independent murine APL and AML models acquire del(2), implicating del(2) as an important event in murine AML progression. In addition, up to 14% of relapsed APL patients develop a deletion or translocation on human chromosome 11, syntenic to the mouse del(2) region. Therefore, understanding the mechanism of leukemia progression in murine del(2) models will likely aid the investigation of AML and MDS in humans with similar chromosomal changes. In this proposal, we will assess the importance of del(2) for AML progression by creating mice with del(2) using homologous recombination and Cre/loxP technology, and analyze the phenotype of these mice (Specific Aim 1). We will intercross del(2) mice from Specific Aim 1 with hCG-PML-RAR( mice, and investigate the mechanisms associated with leukemia progression (Specific Aim 2). We will characterize the importance of del(2) for AML progression by evaluating the latency, penetrance, and phenotype of leukemias arising in intercrossed mice. We will systematically evaluate the hematopoiesis of these mice and investigate potential mechanisms associated with leukemia progression.